Compositions and methods for inducing appendage and limb regeneration

Abstract

Disclosed herein include methods, compositions, and kits suitable for use in inducing reparative regeneration and/or appendage regeneration. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of one or more amino acids and a therapeutically effective amount of one or more sugars, and thereby inducing reparative regeneration or appendage regeneration in the subject. There are provided, in some embodiments, regenerative agents suitable for use in the methods provided herein. Regenerative agents can stimulate mTOR signaling and/or insulin signaling. Regenerative agents can include one or more amino acids, insulin, and/or one or more sugars.

1 . A method for inducing reparative regeneration or appendage regeneration, comprising administering to a subject in need thereof a therapeutically effective amount of one or more amino acids and a therapeutically effective amount of one or more sugars, and thereby inducing reparative regeneration or appendage regeneration in the subject. 
     
     
         2 . A method for inducing reparative regeneration, comprising administering to a subject in need thereof:
 a therapeutically effective amount of a first regenerative agent or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or prodrug thereof, that stimulates mTOR signaling; and   a therapeutically effective amount of a second regenerative agent or a pharmaceutically acceptable salt, ester, solvate, stereoisomer, tautomer, or prodrug thereof, that stimulates insulin signaling, and thereby inducing reparative regeneration in the subject.   
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 2 , wherein the first regenerative agent comprises MHY1485, 3BDO, CL316,243, one or more amino acids, or any combination thereof. 
     
     
         5 .- 7 . (canceled) 
     
     
         8 . The method of  claim 4 , wherein the one or more amino acids comprises alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutylic acid, cirtulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, tert-butylglycine, 3,5-dibromotyrosine, 3,5-diiodotyrosine, glycosylated threonine, glyclosylated serine, glycosylated asparagine, or any combination thereof. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 4 , wherein the one or more amino acids comprises L-leucine. 
     
     
         12 . (canceled) 
     
     
         13 . The method of any  claim 2 , wherein the second regenerative agent comprises an insulin receptor agonist. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 2 , wherein the second regenerative agent comprises insulin and/or one or more sugars. 
     
     
         16 . The method of  claim 15 , wherein the one or more sugars comprise a monosaccharide, a disaccharide, a polysaccharide, or any combination thereof. 
     
     
         17 . The method of  claim 15 , wherein the one or more sugars comprise sucrose, dextrose, maltose, dextrin, xylose, ribose, glucose, mannose, galactose, sucromalt, fructose (levulose), or any combination thereof. 
     
     
         18 . The method of  claim 2 , wherein the second regenerative agent increases insulin secretion. 
     
     
         19 . The method of  claim 2 , wherein the subject in need is a subject suffering from or at a risk to develop a disease or disorder, wherein the disease or disorder results in damage, injury, or loss of a limb, organ, tissue, cell, or any combination thereof. 
     
     
         20 . The method of  claim 2 , wherein the subject in need is suffering from an acute injury. 
     
     
         21 .- 24 . (canceled) 
     
     
         25 . The method of  claim 2 , wherein the reparative regeneration comprises regeneration of one or more tissues. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 2 , wherein the reparative regeneration and/or appendage regeneration is patterned. 
     
     
         29 .- 34 . (canceled) 
     
     
         35 . The method of  claim 2 , wherein the second regenerative agent is administered before initiating administration of the first regenerative agent. 
     
     
         36 . The method of  claim 2 , wherein the administration of the first regenerative agent continues after cessation of administration of the second regenerative agent, and/or wherein the administration of the second regenerative agent continues after cessation of administration of the first regenerative agent. 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . The method of  claim 2 , wherein the administration of one or both of the first and second regenerative agents is initiated within a therapeutically effective time window. 
     
     
         40 .- 57 . (canceled) 
     
     
         58 . The method of  claim 2  any one of  claims 1   57 , comprising administering a third regenerative agent that activates mTOR signaling. 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . The method of  claim 2 , wherein the method does not induce insulin resistance. 
     
     
         62 . The method of  claim 2 , wherein the method comprises contacting the subject in need with a scaffold,
 wherein the scaffold comprises a bandage, beads, a hydrogel, a polymer, or other biomaterial, or any combination thereof; and   wherein the scaffold comprises a bone morphogenetic protein (BMP), a hormone, a growth factor, or other agent that induces reparative regeneration and/or appendage regeneration, or any combination thereof.   
     
     
         63 . (canceled)